ABSTRACT Antiretroviral therapy (ART) has resulted in people living with HIV (PLWH) now aging with prolonged survival, yet high rates of complications and comorbid conditions. This is due to a complex interplay between HIV infection, host genetics, and traditional risk factors leading to comorbidities. Understanding the role of genetic modification of drug responses to specific ART combinations through pharmacogenetic (PGx) evaluation could improve drug efficacy, mitigate ART-related side effects and reduce comorbidities. Discovering informative ART-PGx variants could not only help identify PLWH at risk for ART-associated adverse events and comorbidities, but also anticipate side effects of nascent ART combinations. However, despite lifelong need for ART, no comprehensive analysis of the role of genetic variation among PLWH in clinical care on combination ART regimens have been conducted to better understand the wide variety of adverse clinical outcomes they experience. We will use CNICS (Centers for AIDS Research Network of Integrated Clinical Systems), a large well-characterized prospective cohort of PLWH in care in the U.S with in-depth longitudinal clinical data including medications, health behaviors, laboratory test results, and validated and adjudicated diagnoses. In this largest genetic study in PLWH to date, we will characterize the genetic landscape of a variety of adverse side effects associated with ART regimens using existing genome-wide array data and newly generated next generation sequencing data from ethnically/racially diverse phenotypic extremes. We will also use the systems pharmacology approach to identify specific ART-induced pathways that are involved in the pathogenesis of adverse events using relevant cell model systems. We will test the hypothesis that the increased risk of adverse effects and comorbidities associated with ART can be explained, at least in part, by a burden of common and/or low frequency genetic variants that exacerbate ART effects. Aim 1: Conduct a genome-wide screening of variants that modify ART efficacy, including change in CD4 and viral load; ART tolerability, including renal and hepatic toxicity, and ART-associated adjudicated comorbidities in ~14,000 PLWH from the CNICS cohort. The significant findings will be validated in independent cohorts; Aim 2: Identify biological pathways and related key driver genes through which various ART regimens promote adverse events using a systems pharmacology approach and validate the findings in clinical cohorts, and Aim 3: Using novel technologies, determine individual PGx gene profiles associated with ART-induced diverse adverse clinical phenotypes by sequencing PLWH with the most severe toxicities, poor efficacy and tolerability, and adverse effects or comorbidities. The proposed studies promise to enhance our understanding of the biological mechanisms of ART response, helping reduce HIV-related complications. Identification of genetic modifiers of combination ART regimens is an important step towards risk stratification, prevention strategies and tailored treatment options for PLWH, ultimately helping develop a strong evidence base for personalized medicine.